Increasing attention has been focused on skeletal muscle as a target tissue for gene transfer both for the production of proteins that may be therapeutic for muscle disorders and the systemic delivery of non-muscle proteins. Although the engineering of new mutant muscle proteins and the systemic delivery of non-muscle proteins. Although the engineering of new mutant vectors has reduced the problems associated with viral cytotoxicity and immune rejection, the inability of viral vectors to efficiently transduce mature muscle fibers has remained a major barrier to the application of gene transfer to skeletal muscle. Results from our laboratory and others have shown that adenovirus efficiently transduces neonatal muscle; however, within a few days of mouse development, the muscle is largely refracted to adenoviral transduction. Here we present a series of preliminary results and proposed research protocols aimed at defining the barriers to adenoviral transduction of mature muscle. We then plan to investigate methods by which these barriers can be overcome. The proposed research should define and eliminate a major hurdle facing the application of viral gene delivery to skeletal muscle to enable efficient application of muscle-based gene therapy for both inherited and acquired diseases.